Telomere Length and Telomerase Activity Impact the UV Sensitivity Syndrome Xeroderma Pigmentosum

2015-01-13

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Abstract
Xeroderma pigmentosum (XP), a UV-sensitivity syndrome characterized by skin hyperpigmentation, premature aging, and increased skin cancer, is caused by defects in the nucleotide excision repair (NER) pathway. XP shares phenotypical characteristics with telomere-associated diseases like Dyskeratosis congenita and mouse models with dysfunctional telomeres, including mice deficient for telomerase (Terc-/- mice). Thus, we investigated a hypothesized role for telomerase and telomere dysfunction in the pathobiology of XP by comparing Xpc-/--mutant mice and Xpc-/-G1-G3Terc-/- double-mutant mice and exposed them to UV radiation. Chronically UV-exposed Xpc-/- skin displayed shorter telomeres on an average compared with wild-type skin. Strikingly, this effect was reversed by an additional deficiency in the telomerase. Moreover, aberrantly long telomeres were observed in the double-mutant mice. Telomere lengthening in the absence of telomerase suggested activation of the alternative lengthening of telomeres (ALT) in the UV-exposed skin of the double mutants. Mechanistic investigations revealed an elevated susceptibility for UV-induced p53 patches, known to represent precursor lesions of carcinomas, in Xpc-/-G1-G3Terc-/- mice where a high number of UV-induced skin tumors occurred that were characterized by aggressive growth. Taken together, our results establish a role for xeroderma pigmentosum, complementation group C (XPC) in telomere stability, particularly upon UV exposure. In absence of telomerase, critically short telomeres in XP mutants seem to aggravate this pathology, associated with an increased tumor incidence, by activating the ALT pathway of telomere lengthening

Some notes
-Cancer Research journal
-CNIO paper
-Gerdine Stout and Maria Blasco paper
-corresponding author is Gerdine Stout
-Thus, we investigated a hypothesized role for telomerase and telomere dysfunction in the pathobiology of XP by comparing Xpc-/--mutant mice and Xpc-/-G1-G3Terc-/- double-mutant mice and exposed them to UV radiation.
-XP <- defects in the nucleotide excision repair (NER) pathway
-
Moreover, aberrantly long telomeres were observed in the double-mutant mice. Telomere lengthening in the absence of telomerase
suggested activation of the alternative lengthening of telomeres (ALT) in the UV-exposed skin of the double
mutants.
--surprising result
-q
In absence of telomerase, critically short telomeres in XP mutants seem to aggravate this pathology, associated
with an increased tumor incidence, by activating the ALT pathway of telomere lengthening. 
-knockout mice
-UVB carcinogenesis
-Q-FISH
-cytogenetic analysis
-ImmunoFISH
-Xpc prevents telomere fragility
-Longevity and aging in XpcTerc mouse model
-UV-induced carcinogenesis is accelerated in XpcTerc
mice
-Chronic UV exposure leads to accelerated telomere
shortening
-Immunohistochemistry on UV-irradiated skin
-Activation of ALT in UV-irradiated skin of Xpc / Terc  / 
skin

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